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A Fat-Tissue Sensor Couples Growth to Oxygen Availability by Remotely Controlling Insulin Secretion

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A Fat-Tissue Sensor Couples Growth to Oxygen Availability by Remotely Controlling Insulin Secretion ARTICLE https://doi.org/10.1038/s41467-019-09943-y OPEN A fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion Michael J. Texada 1, Anne F. Jørgensen 1,2, Christian F. Christensen1, Takashi Koyama 1, Alina Malita1, Daniel K. Smith1, Dylan F. M. Marple1, E. Thomas Danielsen 1, Sine K. Petersen1, Jakob L. Hansen2, Kenneth A. Halberg 1 & Kim F. Rewitz 1 Organisms adapt their metabolism and growth to the availability of nutrients and oxygen, 1234567890():,; which are essential for development, yet the mechanisms by which this adaptation occurs are not fully understood. Here we describe an RNAi-based body-size screen in Drosophila to identify such mechanisms. Among the strongest hits is the fibroblast growth factor receptor homolog breathless necessary for proper development of the tracheal airway system. Breathless deficiency results in tissue hypoxia, sensed primarily in this context by the fat tissue through HIF-1a prolyl hydroxylase (Hph). The fat relays its hypoxic status through release of one or more HIF-1a-dependent humoral factors that inhibit insulin secretion from the brain, thereby restricting systemic growth. Independently of HIF-1a, Hph is also required for nutrient-dependent Target-of-rapamycin (Tor) activation. Our findings show that the fat tissue acts as the primary sensor of nutrient and oxygen levels, directing adaptation of organismal metabolism and growth to environmental conditions. 1 Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark. 2 Cardiovascular Research, Department number 5377, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark. Correspondence and requests for materials should be addressed to K.F.R. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:1955 | https://doi.org/10.1038/s41467-019-09943-y | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-09943-y ulticellular organisms must adapt their metabolism and manipulating Btl-mediated tracheal outgrowth or external O2 Mgrowth to limitations imposed by their environment. levels, or genetically inducing ectopic hypoxia responses via Hph Genetic and physiological pathways such as growth or HIF-1a perturbation, alters the expression of Dilp2, -3, and -5 factor systems regulate these adaptations, and these in turn are in the IPCs and blocks DILP release, leading to reduced systemic influenced by internal and external cues. Among these are insulin signaling. We further report that the primary sensor of nutrient availability, which promotes growth through the insulin/ internal oxygen availability is the fat body. Both hypoxia and insulin-like growth factor (I/IGF) pathways1,2, and oxygen suffi- amino acid (AA) insufficiency block Hph activity in this tissue, ciency, which is also essential for the growth and development and this effect propagates through two divergent pathways of animals3,4. The signaling pathways that regulate these funda- downstream of Hph: HIF-1a-independent inhibition of the mental aspects of development are evolutionarily ancient and Tor pathway alters adipose-tissue physiology, whereas a Tor- well conserved. independent, HIF-1a-dependent pathway leads to the release of I/IGF is the major systemic nutrient-dependent growth reg- one or more humoral factor(s) that strongly inhibit DILP release ulator and acts through conserved pathways to promote cellular and thereby adapt organismal growth to oxygen availability. growth5,6. Many connections between nutritional cues and sys- Thus, Hph/HIF-1a and Hph/Tor pathways in the fat body temic insulinergic regulation have been elucidated in the fruit function as central integrators of both oxygen and AA levels to fly Drosophila melanogaster. Several Drosophila insulin-like pep- adapt growth and metabolism to environmental conditions. tides (DILPs or simply insulin below), primarily DILP2, -3, and Understanding the changes brought about by hypoxia in this -5, are released into circulation from the insulin-producing cells model system may allow greater understanding of human disease (IPCs) of the brain7. Despite their different location, these cells associated with tissue hypoxia such as obesity and diabetes. are functionally homologous with mammalian pancreatic β-cells8. The DILPs signal through a single receptor (InR) to regulate Results both metabolism and growth. DILP expression and release are In-vivo RNAi screen for signals affecting body size.We regulated in part by nutritional information relayed through the undertook a genetic RNAi31,32 screen targeting 1845 genes fat body, an organ analogous to vertebrate adipose and liver tis- encoding the Drosophila secretome and receptome (Fig. 1a, sues with nutrient storage, metabolic, and endocrine functions. Supplementary Data 1). Ubiquitous knockdown using the This tissue secretes insulinotropic (Unpaired-2, functionally daughterless-GAL4 driver (da>) identified 89 genes whose analogous to the mammalian adipokine Leptin9; the peptide fi 10 11 manipulation resulted in signi cant size phenotypes (Fig. 1b, c). hormones CCHamide-2 (CCHa-2) , FIT , and Growth- Among these were several genes associated with body or tissue Blocking Peptides (GPBs) 1 and 212,13; the Activin ligand Daw- 33 14,15 16 growth including Insulin receptor (InR) , Anaplastic lymphoma dle (Daw) ; and the protein Stunted (Sun) ) and insulino- kinase (Alk)34 and jelly belly (jeb)35, Epidermal growth-factor α 17 static (the tumor necrosis factor- homolog Eiger (Egr) ) factors, receptor (Egfr)36, and the prothoracicotropic hormone many of these in response to nutrient-dependent activity of (PTTH) receptor torso37, thus validating our approach. Genes the Target-of-rapamycin (Tor) pathway. Thus, this tissue is a important for ecdysone signaling (knirps, Eip75B, Npc2g, and central nexus for nutritional signals that mediate adaptation to torso37–40) were among the hits that increased pupal body size, nutritional deprivation. consistent with the growth-limiting effects of ecdysone, whereas Organisms require oxygen in addition to nutrients for growth knockdown of the growth-promoting InR produced a strong and development and have therefore developed oxygen-sensing decrease in size. We identified FGF-pathway signaling (Supple- and adaptation mechanisms. In Drosophila and many other mentary Fig. 1) among the strongest hits associated with reduced organisms, hypoxia (low oxygen) restricts systemic growth and 3,18–22 growth. The main hit, the FGFR ortholog btl, and its FGF-like reduces body size , and in humans the limited oxygen ligand Bnl, are critical for proper tracheation of tissues to allow associated with high-altitude living has been linked to slow for gas exchange and oxygen delivery28. growth and developmental delay23,24. These effects occur at oxygen concentrations above those that compromise basic metabolism25,26, indicating that they do not reflect limited FGF signaling affects systemic growth via tracheal effects. aerobic respiration but rather an active adaptation under genetic Ubiquitous btl (da > btl-RNAi)andbnl (da > bnl-RNAi)knockdown strongly reduced growth and pupal size (Fig. 2a, b). Knockdown of control. The conserved transcription factor hypoxia-inducible 41 factor 1 alpha (HIF-1a) is the key regulator required for these the upstream transcription factor trachealess (trh) , also required for tracheal formation, reduced body size to a lesser degree, perhaps adaptive responses. At a rate proportional to oxygen levels, it is fi marked for degradation by HIF-1a prolyl hydroxylase (Hph)27. because of low RNAi ef ciency or Trh-independent signaling later in development42. btl is mainly expressed in the tracheal system but Thus, under hypoxic conditions, HIF-1a is able to perdure and 43 (with its constitutively present beta subunit) induce target-gene it is also active in other cells .Toidentifythetissuecausingthe expression. Although it is well established that nutrients mainly size phenotype, we assayed effects of btl RNAi in the tracheae (btl > affect growth through insulin, the mechanism by which animals btl-RNAi), neurons (elav>), musculature (Mef2>), fat body (ppl>), and glia (repo>). Only tracheal knockdown of btl led to reduced adaptively limit growth under oxygen limitation remains to be fi fi determined. body size (Fig. 2c). RNAi speci city was con rmed with two We describe here an RNA interference (RNAi)-based screen additional independent btl-RNAi lines (Supplementary Fig. 2a). for body-size defects, covering genes encoding potential secreted Knockdown of btl in the tracheae delayed pupariation, thus factors and their receptors, in which we identify breathless (btl)28, prolonging the larval growth period, suggesting that small size encoding a fibroblast growth factor receptor (FGFR) homolog, as resulted from reduced growth rate (Supplementary Fig. 2b). We one of the strongest hits. This receptor is expressed by cells of the therefore measured the growth rate during the third larval instar tracheae, the gas-delivery tubules of the insect respiratory system. (L3) and found indeed that tracheal btl RNAi systemically slowed Its FGF-like ligand Branchless (Bnl) is produced by target tissues body growth (Fig. 2d). Thus, btl is required in the tracheal system in a stereotyped pattern and in response to tissue hypoxia during for normal systemic growth, possibly via effects on oxygen delivery. development29,30 to guide the tracheal terminal branches toward target tissues. When this system is perturbed, internal tissues The btl-RNAi size phenotype
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